Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease

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Abstract
Alexander disease is a progressive, usually fatal neurological disorder defined by the widespread and abundant presence in astrocytes of protein aggregates called Rosenthal fibers. The disease most often occurs in infants younger than 2 years and has been labeled a leukodystrophy because of an accompanying severe myelin deficit in the frontal lobes. Later onset forms have also been recognized based on the presence of abundant Rosenthal fibers. In these cases, clinical signs and pathology can be quite different from the infantile form, raising the question whether they share the same underlying cause. Recently, we and others have found pathogenic, de novo missense mutations in the glial fibrillary acidic protein gene in most infantile patients examined and in a few later onset patients. To obtain further information about the role of glial fibrillary acidic protein mutations in Alexander disease, we analyzed 41 new patients and another 3 previously described clinically, including 18 later onset patients. Our results show that dominant missense glial fibrillary acidic protein mutations account for nearly all forms of this disorder. They also significantly expand the catalog of responsible mutations, verify the value of magnetic resonance imaging diagnosis, indicate an unexpected male predominance for the juvenile form, and provide insights into phenotype–genotype relations. Ann Neurol 2005;57:310–326
Funding Information
  • NIH (National Institute of Neurological Disorders and Stroke) (P01NS42803, RO1NS39055)
  • Mental Retardation Research Center (P30HD38985)
  • Lei Foundation
  • United Leukodystrophy Foundation
  • National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders under National Institute of Child Health and Human Development (N01-HD-43368, NO1-HD-8-3284)
  • National Neurological Research Specimen Bank
  • National Institute of Neurological Disorders and Stroke/National Institute of Mental Health
  • National Multiple Sclerosis Society
  • Hereditary Disease Foundation
  • Veterans Health Services and Research Administration, Department of Veterans Affairs